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CHAPTER-I
Introduction to five and ten membered lactone natural products
Introduction to five and ten membered lactone natural products
Synthesis is a very important area to all parts of chemistry.1 It
encompasses the distinctive capability of chemists to develop new
methods and to design molecules with a preferred set of properties. The
practical and inventive nature of the ‘chemical synthesis’ is distinctive
among all of the physical sciences. This is particularly true of research in
the synthesis of natural products. Although various techniques are
available to the natural product isolation chemists, it is not possible all
the time to establish the complete structure and stereochemistry of
natural product based on the spectroscopic techniques. Hence, chemical
synthesis is very useful method and plays an important role in
determination of structure.
The field of synthesis of natural products has been acknowledged
with the Nobel Prize in chemistry with regular recurrence over the whole
history of the award. These prizes have been awarded to E. Fischer
(1902) for the syntheses of purine and sugar, H. Fischer (1930) for his
research on the constitution of chlorophil, haemin and particularly for
the haemin synthesis, R. Robinson (1947) for his explorations on
biological importance of plant products, specifically the alkaloids, R. B.
Woodward (1965) for the outstanding accomplishment on the art of
organic synthesis and E. J. Corey (1990) for his theory and methodology
development of organic synthesis. Recently, the field of organic synthesis
comes into view as imperative as ever, and its prospect appears as
proficient as its history has been gratifying. There are several motivations
why the synthesis of natural products endured the test of time as a
rewarding and facilitating science and technology, its attractiveness as
an inventive and intellectual effort offering possibilities for discovery.
Even though the topic of synthesis of natural product is attracting a
vigorous attention in research laboratories all over the world today, the
causes for practicing it show a discrepancy. In general isolation of
natural product is in small amount, however biologically interesting.
Hence the synthesis of natural product in larger extent is important for
further extensive evaluation of medicinal or biological properties.
Furthermore the synthesis of a natural product still gives the absolute
evidence of the assigned structure. Finally, there are those who will
courageously and proudly declare that they enter campaign of total
synthesis for the intellectual challenge and complete exhilaration of the
endeavor. Due to this exciting information, we became involved in the
synthesis of biologically active compounds as a part of our research
work.
1.1. Five membered lactones:
Five membered lactone (γ-lactone) containing natural products are
known to exhibit various of biological activities2 such as cytotoxic,3
antitumor,4 cyclooxygenase or phospholipase A2 inhibition.5 These are of
fungal, bacterial or marine source. The natural products with γ-lactone
motif also showed valuable pharmacological properties. Biological
properties, structural complexities of γ-lactone molecules, and challenges
to synthesize in optically pure form, which are made them an attractive
target for various total syntheses. Isolation and biological properties of
some γ-lactone containing natural products are described below.
(R)-5-((S,2Z,4E)-1-hydroxydeca-2,4-dienyl)dihydrofuran-2(3H)-one
(1):6 It is a γ-lactone containing unsaturated side chain and hydroxy
group. The compound 1 was isolated from Lithophiton arboretum by
Tomas Rezanka et al. and it exhibits strong antibacterial activity against
Staphylococcus aureus (MIC = 7.8 µg/ml). The structure of 1 was
established by spectroscopic analysis and absolute configuration
determined by Mosher’s ester method.
OH
O
O
(R)-5-((S,2Z,4E)-1-hydroxydeca-2,4-dienyl)dihydrofuran-2(3H)-one (1)
Hamabiawalactone B (2) and akolactone B (3): Hyeong Kyu Lee et al.
isolated Hamabiawalactone B (2) and Akolactone B (3) from the leaves of
Litsea japonica.7 The molecules 2 and 3 found to have potent anti-
complement activity with IC50 values of 149 and 58 µg/ml respectively,
when compared to rosmarinic acid (IC50, 180 µg/ml), which was utilized
as a positive control.
O
O
O
O
Hamabiawalactone (2)
Akolactone (3)
Sapinofuranones A and B (4 and 5): Two novel 5-substituted
dihydrofuranones, apinofuranones A and B (4 and 5),8 were isolated from
liquid cultures of Sphaeropsis sapinea, which is a phytopathogenic
fungus causing a variety of infection symptoms on conifers. They exhibit
more phytotoxic activity on internal bark tissues than on peripheral
ones. The structures of molecules were established by spectroscopic
analysis and absolute configuration determined by Mosher’s ester
method.
R1=OH, R2=H
R1=H, R2=OH
Apinofuranones A (4)
Apinofuranones B (5)
R1
R2
O
O
(+) Cardiobutanolide (6): The (+) cardiobutanolide9 (6) was isolated from
the stem bark of Goniothalamus cardiopetalus. The plant Goniothalamus
cardiopetalus exhibits a variety of therapeutic actions in traditional
medicine to cure the edema, rheumatism, and as mosquito repellents.
The structure of compound was established by spectroscopic methods.
OH
OH
OH
O
O
OH
(+) Cardiobutanolide (6)
Syributin 1 (7) and Syributin 2 (8): Sims et al. isolated syributin 1 (7)
and syributin 2 (8)10 along with secosyrins, as co-isolates of syringolide
from Pseudomonas syringe. The plant from which these compounds
isolated, exhibited a variety of medicinal activities. The structures of
compounds were established by spectral methods.
O
O
O
O
OH
OH
O
O
O
O
OH
OH
Syributin 1 (7) Syributin 2 (8)
Sapinofuranones (9, 10 and 11): Simpson et al. isolated a novel
metabolite sapinofuranone B11 (9) from fermentation extracts of
Saphaeropsissapinae. Subsequently, closely related lactones
sapinofuranone A (10) and ent-sapinofuranone B (11) were isolated from
Saphaeropsissapinae liquid cultures.
O O
OHO O
OH
O O
OH
Sapinofuranone B (9) Sapinofuranone A (10)
ent-sapinofuranone B (11)
(4R,9Z)-9-Octadecen-4-olide (12):
(4R,9Z)-9-Octadecen-4-olide (12) is the female sex pheromone of
the female currant stem girdler, Janus integer, which is an occasional
pest of red currant in North America and was isolated by Cosse et al. The
compound 12 was isolated as a single enantiomer and its absolute
configuration was proposed as R-configuration by a bioassay of synthetic
samples.12
O
O
C8H
17
(4R,9Z)-9-Octadecen-4-olide (12)
Muricatacin (13): J. L. McLaughlin et al. isolated muricatacin (13) as a
novel metabolite from Annona muricata. The antitumor activities in
addition to the patented pesticidal applications of the bark and seed
extracts from this family hold admirable prospective for development.
The structure of 13 was established by spectral methods.13
O
O
OH
Muricatacin (13)
Iso-cladospolide-B (14): Ireland et al. isolated iso-cladospolide-B (14) 14
from a tissue sample of a marine sponge. The structure was determined
by spectral methods and the absolute configuration was established by
its total synthesis.
OH
O
O
OH
Iso- cladospolide B (14)
(+)-Luffalactone (15): De Silva et al. isolated (+)-luffalactone (15) from
marine sponge Luffariella variabilis. It exhibits strong anti-inflammatory
activity. The structure was determined by spectral studies and the
absolute configuration at C-16 was established by Pilar Basabe et al. in
2009, by synthesis of the (+)-luffalactone.15
O
O
AcOO
O
(+)-Luffalactone (15)
Botryolides E (16): James B. Gloer et al. isolated botryolide E (16) from
the cultures of a fungicolous isolate of Botryo trichum sp. (NRRL 38180),
in 2008.16 The structure was determined by spectral data. The absolute
configuration of 16 was determined by modified Mosher’s method.
O OH
O
O
O
Botryolide E (16)
Pectinolide H (17): R. Perda-Miranda et al. isolated pectinolide H from
the chloroform extract of the aerial parts of a Mexican terrestrial plant
Hyptis pectinata. It displays strong antimicrobial activity against a panel
of multidrug-resistant strains of Staphylococcus aureus. 17
OAc OH
OO
Pectinolide H (17)
1.2. Ten membered ring containing macrolides
Natural products containing a macrolactone structure can be
originated in bacteria, plants, insects and they may be of marine or
terrestrial source. The valuable activities of macrolides vary from
perfumery to medicinal and biological properties. The new results in the
field of antibiotic and other antitumor active macrolides, accompanied by
pheromones and plant growth regulators with macrolactone skeleton, are
a motivation to chemists to study macrolides.
In relation to lactone structures and biosynthesis, these are
classified into monocyclic oxylipins, monocyclic polyketides, aromatic
bicyclic and aliphatic bicyclic lactones. In every subsection, these
macrolides are explained in sequential order of their isolation.
1.2.1. Diplodialides:
Diplodialides (18-21) are monocyclic ten-membered-ring
containing lactones. In 1975, diplodialides A, B and C were isolated by
Ishida and Wada, from the plant pathogenic fungus Diplodia pinea.18 The
isolation of diplodialide D (21)19 and the structural elucidation of the
metabolites,20 were established by the same authors. (+) Diplodialide A
(18) exhibited inhibitory activity against steroid 31674 hydroxylase.
1.2.2. Phoracanthonolides: The phoracanthonolides I (22) and J (23)
were isolated from the secretion of the metasternal gland of eucalypt
longicorn Phoracantha synonyma in 197621 and are structurally simple
decalactones.
1.2.3. Pyrenolides: Pyrenolides A, B and C (24–26) were isolated by
Nukina group, from the Pyrenophora teres22,23 in 1980. Pyrenolide A also
isolated from culture filtrates of Ascochyta hyalospora24 in 1992. These
show morphogenic and growth inhibition activities against fungi.
O
O
O
O
O
HO
(+)-Diplodialide A (18) (-)-Diplodialide B (19)
O
O
HO
O
O
HOO
(+)-Diplodialide C (20) Diplodialide D (21)
12
3
45
67
8910
O
O
O
O
(-)-Phoracanthonolide I (22) (-)-Phoracanthonolide J (23)
O
O
O
O
O
O
O
O
OH
OO
(-)-Pyrenolide A (24) (-)-Pyrenolide C (26)(-)-Pyrenolide B (25)
1.2.4. Decarestrictines: A series of metabolites were generated by
various strains of Penicillium species were isolated in the early 1990s and
called as decarestrictines. These lactones exhibited to be inhibitors of
cholesterol biosynthesis and explained by both in vivo and in vitro
studies.25
Most of the decarestrictines consist of ten-membered lactone
moiety that varies in the oxygenation mold between C3 and C7. Five of
them bear an epoxide function at C6–C7 such as A1 (27), A2 (28), B (29),
E (30), and F (34), and eight of them A1 (27), A2 (28), C1 (31), C2 (32), D
(33), F (34), H (36), K (38) contain a double bond, and seven of the
decarestrictines B (29), E (30), F (34), G (35), H (36), J (37), K (38) are β-
keto lactones.
The most biologically active decarestrictine D (33), was individually
isolated from the Canadian Tuckahoe, the sclerotium of the Polyporus
tuberaster fungus and called as tuckolide.26
A C6-epimer of decarestrictine C1 was obtained from the fungus
Cordyceps militaris.27 Multiplolides A and B, the lactones with epoxy ring
(40 and 41) were isolated from Xylaria multiplex, and are closely
correlated with the decarestrictine family.28
O
O
O
O R
O
O
O
O
O O
OH
HOOH
HO O OH
OH
HO
(+)-B R = H (29)
(-)-E R = CH3 (30)
(-)-D (33)
A2 (b-OH) (28)
A1 (a-OH) (27) C1 (b-OH) (31)
C2 (a-OH) (32)
1.2.5. Aspinolides:
Aspinolides A–C (42-44) were isolated from the cultures of Aspergillus
ochraceus, in 1997. The absolute configuration and structure elucidation
evaluated by X-ray alalysis and Helmchen’s method.29
Aspinolides are characterized by the occurrence of a
methylcarbinol moiety in their structures and their C9-center is usually
with the (R)-configuration, represents the starter unit in the polyketides
biosynthesis.30
O
O
O
O
O
O
O
O
O O O O
O OHOH
OH OH
F (34) (-)-G (35)H (36) (-)-J (37)
O
O
O
O
O
O
O
O
OOH
HO
OH OH
OOH
OH
OO
O
6-epi -C1 (39) Multipolide A (40)K (38) Multipolide B (41)
O
O
O
HO
O
O
O
O
HO
HO
O
O
O
HO
O
Aspinolide A (42) Aspinolide B (43) Aspinolide C (44)
1.2.6. Pinolidoxins: Pinolidoxin (45), a decalactone isolated by evidente
et. al from Ascochyta pinoda in 1993,31 and also three similar macrolides,
dihydropinolidoxin (47), epipinolidoxin (46) and epoxypinolidoxin (48)
were isolated32 and evaluated on bean and pea leaves, initial three
molecules were exhibited to be highly toxic, but epoxypinolidoxin was
inactive.
1.2.7. Herbarumins: Rivero-Cruz et al.33,34 isolated three hexaketides
from fungus Phoma (P. herbarum), and named as herbarumins I–III (49-
51). These macrolides interact with the calmodulin of bovine brain and
inhibit the cAMP phosphodiesterase enzyme activation.
O
O
OHO
HOO
O
O
OHO
HOO
O
O
OHO
HOO
O
(+)-Pinolidoxin (b-OH) (45)(+)-Epipinolidoxin (a-OH) (46)
Dihydropinolidoxin (47)
Epoxypinolidoxin (48)
O
O
HO
HO
O
O
OHHO
HO
O
O
HO
(+)-Herburamin I (49) (+)-Herburamin II (50) (+)-Herburamin III (51)
1.2.8. Microcarpalide: In 2001, Hemscheidt et al. isolated
microcarpalide (52) from the fermentation broths of an unknown
endophytic fungus.35 This molecule works as a microfilament-disrupting
agent, and it shows weak cytotoxic activity against mammalian cells. It
molecular formula similar with achaetolide (53)36, but differs in the
position of the double bond and the hydroxy groups.
1.2.9. Stagonolides: Evidente37,38 et al. isolated new phytotoxic
metabolites from Stagonospora cirsii, which is a fungal pathogen isolated
from Cirsium arvense and anticipated as a prospective mycoherbicide of
this perennial toxic weed, generates phytotoxic metabolites in solid and
liquid cultures. Stagonolides A-D (54-57), with remarkable phytotoxic
activities were isolated from a liquid culture. The same fungus, grown-up
in solid culture, showed an improved ability to produce five new
nonenolides, called stagonolides E-I (58-62).
OO
C6H13
OH
OH
OH
OO
C7H15
OH
OH
HO
(-)-Microcarpalide (52) (-)-Achaetolide (53)
1.2.10. Didemnilactones and Ascidiatrienolides:
In the early 1990s, Niwa et al. isolated didemnilactones A and B
(63 and 64), ascidiatrienolide A and neodidemnilactone (65 and 66). 39,40
These eicosanoid lactones were isolated from the marine tunicate
Didemnum moseleyi, and exhibited modest inhibitory activity toward
lipoxygenase.
O
O
O
OHO
O
OH
OH
OH
O
O
OH
OH
O
O
H
H
OH
O O
O
OH
OO
OH
Stagonolide A (54) Stagonolide B (55) Stagonolide C (56)
Stagonolide D (57) Stagonolide E (58) Stagonolide F (59)
O
O
OH
OHO
O
H
H
OH
O
O
O
OHHO
Stagonolide G (60) Stagonolide I (62)Stagonolide H (61)
O
OH
O
O
OH
O
(-)-Neodidemnilactone (66)(-)-Ascidiatrienolide A (65)
O
OH
O
O
O H
O
(-)-D idemnilactone A (63) (-)-Didem nilactone B (64)
1.3. Mueggelone or Gloeolactone:
A lactone with 18-carbons and epoxy group (67) was isolated from
the Aphanizomenon flos-aquae, a cyanobacterium in 1997, it was
exhibited to be a fish development inhibitor, and called as mueggelone.41
The same lactone was isolated from the blue-green algae Gloeotrichia sp.,
and was named as gloeolactone.42
OO
O
(+)-Muggelone or gloeolactone(67)
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